Psilocybin vs Escitalopram for Major Depressive Disorder: Comparative Mechanisms

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Sponsors & Collaborators

Imperial College London
The Centre for Psychedelic Research studies the action (in the brain) and clinical use of psychedelics, with a focus on depression.

Alexander Mosley Charitable Trust
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Papers

Reduced brain responsiveness to emotional stimuli with escitalopram but not psilocybin therapy for depression
This pre-print analysis of an RCT (n=59) investigates the impact of psilocybin-assisted therapy (PAT) and escitalopram (SSRI) on responsiveness to emotional stimuli in patients with moderate-to-severe major depressive disorder over a 6-week trial period. Responses to emotional faces were reduced in the SSRI group, not the psilocybin group at the follow-up.

Unique Psychological Mechanisms Underlying Psilocybin Therapy Versus Escitalopram Treatment in the Treatment of Major Depressive Disorder
This reanalysis of a trial (n=59) investigates the mechanisms underlying the efficacy of Psilocybin Therapy (PAT) versus Escitalopram Treatment in patients with depression (MDD) over a 6-week trial period. Acute psychological experiences such as "mystical experience" and "ego dissolution" were found to mediate the effect of treatment condition on depressive response, suggesting a mechanistic role of these experiences in the treatment of depression via PAT.

Assessing expectancy and suggestibility in a trial of escitalopram v. psilocybin for depression
This reanalysis of an RCT (n=55) compared escitalopram and psilocybin (COMP360) for treating depression (MDD). Patients had higher expectancy for psilocybin, but only expectancy for escitalopram predicted therapeutic outcomes. Additionally, pre-treatment trait suggestibility was associated with therapeutic response in the psilocybin arm, suggesting psychedelic therapy may be less vulnerable to expectancy biases, and highly suggestible individuals may be primed for response to psilocybin treatment.

Effects of discontinuation of serotonergic antidepressants prior to psilocybin therapy versus escitalopram for major depression
This post hoc analysis of a recent clinical trial comparing psilocybin to escitalopram with psychological support for depression (MDD) found that discontinuing SSRIs/SNRIs prior to psilocybin treatment led to reduced treatment effects on depression severity measures. However, there were no observed effects on the acute psychedelic experience. The study suggests that discontinuation of SSRIs/SNRIs before psilocybin treatment might impact treatment response.

How does psilocybin therapy work? An exploration of experiential avoidance as a putative mechanism of change
This re-analysis of the psilocybin (25mg) versus escitalopram (antidepressant, 6 weeks) RCT finds that in the psilocybin arm, experiential avoidance reductions led to improvements in mental health outcomes (e.g. depression severity). Note: the trial itself was insignificant on the primary measure of depression.

Psychedelics and the 'inner healer': Myth or mechanism?
This re-analysis of an RCT (n=59) examines the concept of an 'inner healer' effect associated with psilocybin. Participants receiving a high dose of psilocybin (25mg, 2x) reported higher inner healer scores compared to those receiving a placebo (escitalopram). Furthermore, higher inner healer scores in the high-dose group correlated with improved depressive symptoms two weeks post-dosing, suggesting a potential therapeutic mechanism.

Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial
This 6-month follow-up of a Phase II, double-blind, randomized controlled trial (n=59) finds sustained improvements in depressive symptoms for both psilocybin therapy (PT) and escitalopram treatment (ET) for moderate-to-severe major depressive disorder (MDD). PT shows greater improvements in psychosocial functioning, meaning in life, and psychological connectedness compared to ET at the 6-month follow-up.

Body mass index (BMI) does not predict responses to psilocybin
This pooled analysis (n=77) of body mass index (BMI) data from three psilocybin (25mg) trials finds that BMI doesn't predict the intensity of the response to psilocybin. A fixed-dosing schedule (instead of dosage based on weight which is common for MDMA and ketamine) is probably best going forward in psilocybin-assisted trials.

Psychedelics and sexual functioning: a mixed-methods study
This mixed-methods study combines data from two studies, one large naturalistic study (n=261) and one smaller controlled clinical trial (n=59), to investigate the post-acute effects of psychedelics on self-reported sexual functioning. It finds that naturalistic use of psychedelics is associated with improvements in sexual pleasure, communication, satisfaction with one’s partner, and physical appearance. Similarly, a controlled trial comparing psilocybin therapy with the SSRI escitalopram for depression shows that patients treated with psilocybin report positive changes in sexual functioning, unlike those treated with escitalopram.

Personality change in a trial of psilocybin therapy v. escitalopram treatment for depression
This analysis of an RCT (n=59) investigates the impact of psilocybin-assisted therapy (PAT) and escitalopram on personality traits in patients with moderate-to-severe major depressive disorder over a 6-week trial period. Significant decreases in neuroticism, introversion, disagreeableness, and impulsivity, and increases in absorption, conscientiousness, and openness were observed in the PAT group, while similar changes were seen in the escitalopram group.

Effects of psilocybin versus escitalopram on rumination and thought suppression in depression
This analysis (n=59) of the psilocybin vs escitalopram for depression study finds that those in the psilocybin arm of the study significantly decreased rumination. Only those who were in the psilocybin arm and responded (>50% symptom reduction) had reduced thought suppression (rumination was lower in both responder groups). Ego dissolution and psychological insight, for the psilocybin group, correlated with decreases in rumination and thought suppression.

Trial of Psilocybin versus Escitalopram for Depression
This double-blind placebo-controlled study (n=59) compared psilocybin (2x25mg; 3 weeks apart) to escitalopram (SSRI) over a six-week period and found large improvements in depression scores for those suffering from depression (MDD) in both groups. On the main measure of depression, the QIDS-SR-16, there was no significant difference between both groups. The study did find significant differences, favoring psilocybin, on the HAM-D-17, MADRS, avoidance, flourishing, wellbeing, and suicidality.

Measures Used

Quick Inventory of Depressive Symptomatology
The Quick Inventory of Depressive Symptomatology (Self-Report) (QIDS-SR16) is a self-report tool designed to screen for depression and measure changes in the severity of symptoms.